PROJECT SUMMARY/ABSTRACT - PROJECT 1 This project will further our studies of the contribution of cross-reactive anti-DNA anti-N- methyl-D-aspartate receptor (NMDAR) antibodies, denoted DNRAbs, to neuropsychiatric lupus (NPSLE). NPSLE affects approximately 80% of lupus patients and substantially diminishes quality of life. We previously pioneered models for DNRAb-mediated fixed cognitive or behavioral impairment; we will now develop a model of DNRAb-mediated transient impairment. Based on our observation of variable DNRAb concentration in cerebrospinal fluid of lupus patients, we will explore the concentration of tissue-penetrating antibody in reversible and irreversible damage. We will explore the contribution of NMDAR subunit composition to reversible and irreversible damage and will determine whether there can be irreversible injury in the absence of neuronal death. We propose the highly novel hypothesis that microglia are altered in NPSLE as a consequence of ingesting apoptotic neurons and microglial activation functions to sustain neuronal damage. Finally, we will explore therapeutic strategies for preventing irreversible brain injury. These studies will develop new paradigms for antibody-mediated brain disease. We will utilize standard methodologies such as electrophysiology in hippocampal slice preparation, behavioral and cognitive testing and immunocytochemistry. We will pioneer the use of in vivo electrophysiology, microPET studies in a mouse model of NPSLE and RNA-seq of microglial cells.